Method for producing non-hydrated fexofenadine hydrochloride and a novel crystalline form obtained thereby

ABSTRACT

The invention relates to non-hydrated fexofenadine hydrochloride which can be obtained from a fexofenadine base and hydrogen chloride, according to the reaction conditions, either in the form of a novel polymorph (“form A”), in an amorphous form, or in the form of a mixture of different polymorphs. Said novel polymorph (“form A”) can be used as a therapeutic active ingredient and can be processed to form a pharmaceutical containing the same and a pharmaceutically acceptable carrier. Said pharmaceutical is suitable for use as an antihistaminic agent, an antiallergic agent and/or a bronchodilating agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to PCT/CH02/00027, filed Jan. 17, 2002,which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to non-hydrated fexofenadinehydrochloride.

BACKGROUND OF THE INVENTION

Fexofenadine hydrochloride(4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethylphenylaceticacid hydrochloride) has formula (I) below:

and is licensed by the US Food and Drug Administration (FDA) as anantihistamine, antiallergic and bronchodilator under the trade nameAllegra®.

WO-A-95/31437 describes the preparation of hydrated polymorphs, orpseudo-morphs, of fexofenadine hydrochloride (form II and form IV) andtheir conversion to non-hydrated polymorphous forms (form I and formIII) by azeotropic distillation or water-minimizing recrystallization.

WO-A-00/71124 describes amorphous, presumably non-hydrated fexofenadinehydrochloride and its preparation, a spray drying or freeze drying beingcarried out as the final stage.

SUMMARY OF THE INVENTION

It has now been found that non-hydrated fexofenadine hydrochloride canbe prepared from fexofenadine base and hydrogen chloride in a simple anddirect manner, without the need for operations such as azeotropicdistillation, water-minimizing recrystallization, spray drying or freezedrying, to give the non-hydrated fexofenadine hydrochloride in the formof a novel polymorph (“form A”) or in amorphous form or in the form of amixture of different polymorphs, depending on the reaction conditions,wherein

-   (a) fexofenadine base is suspended in a lower alkyl nitrile, a    solution of hydrogen chloride in a lower alkanol, in a di(lower    alkyl) ether or in a lower alkyl ester of a lower alkanecarboxylic    acid is added, and the mixture is heated and then cooled, after    which the non-hydrated fexofenadine hydrochloride is isolated in the    form of the novel polymorph (“form A”), or-   (b) fexofenadine base is suspended in a lower alkane, in a di(lower    alkyl) ether or in a lower alkyl ester of a lower alkanecarboxylic    acid, a solution of hydrogen chloride in a lower alkanol, in a    di(lower alkyl) ether or in a lower alkyl ester of a lower    alkanecarboxylic acid is added, and the mixture is heated and then    cooled, after which the non-hydrated fexofenadine hydrochloride is    isolated in amorphous form, or-   (c) fexofenadine base is suspended in a lower alkyl nitrile,    hydrogen chloride gas is passed into the suspension, and the mixture    is heated and then cooled, after which the non-hydrated fexofenadine    hydrochloride is isolated in the form of a mixture of different    polymorphs.

DETAILED DESCRIPTION OF THE INVENTION

The compounds and radicals referred to above as “lower” appropriatelycontain up to eight carbon atoms. It is preferable to use acetonitrileas the lower alkyl nitrile, methanol as the lower alkanol, diethyl etheror diisopropyl ether as the di(lower alkyl) ether, ethyl acetate as thelower alkyl ester of a lower alkanecarboxylic acid, and n-hexane orn-heptane as the lower alkane.

Fexofenadine base (II) is obtainable in known manner from thehydrochloride of the corresponding keto ester, namely ethyl4-[1-oxo-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethylphenylacetate(III).

The polymorph of fexofenadine hydrochloride obtainable according tovariant (a) of the method according to the invention (“form A”) has amelting range of 153 to 156° C. (DSC) and is characterized by thefollowing XRD data (Table 1):

TABLE 1 XRD data of fexofenadine hydrochloride, form A (d = latticespacing; the relative intensities were taken from the powder diagramobtained using CuK radiation.) rel. intensity d/Å (I/I_(max))/% 11.8 5511.2 30 7.5 50 6.6 30 5.9 20 5.6 70 5.4 20 4.9 65 4.7 100 4.6 35 4.4 404.3 100 4.1 40 4.0 30 3.4 40

This polymorph is novel and also forms a subject of the presentinvention. It can be used as a therapeutic active ingredient andprocessed to a drug containing the active ingredient and apharmaceutically acceptable excipient. This drug is suitable as anantihistamine, antiallergic and/or bronchodilator.

Pharmaceutically acceptable excipients which can be used in thepreparation of drugs are generally known and familiar to all thoseskilled in the art.

By virtue of their different bioavailabilities, rates of release andsolubilities, different forms of a pharmaceutical active ingredient,such as novel polymorphs in particular, can be of great benefit to thepatients in question since they may allow a lowering of the dosageand/or a lengthening of the dosage intervals, making it possible toreduce the costs of the medication.

The Examples which follow will illustrate the invention without in anyway limiting its scope.

EXAMPLES

The XRD spectra were recorded on a Philips ADP1700 computer-controlledpowder diffractometer system with automatic divergence slit andsecondary monochromator (graphite). The CuK_(α) radiation (λ(CuK_(α1))=0.15406 nm and λ (CuK_(α2))=0.15444 nm) from a copper tube(40 kV, 30 mA) was used and the spectra were recorded with Δ(2ΘN)=0.02for a counting time of 3 s in the range 1.5°≦2Θ≦40°.

The differential scanning calorimetry (DSC) measurements were made on aMETTLER DSC 821^(e) apparatus with a start temperature of 25° C., an endtemperature of 250° C. and a heating rate of 10 K min⁻¹. Standardaluminium crucibles with perforated lids were used as the samplevessels. The amount of sample was about 5 mg in each case.

Example 1 Synthesis of Fexofenadine Base

30 g of piperidine derivative III, 1.7 g of sodium borohydride and 7.4 gof sodium hydroxide were suspended in 200 g of ethanol and 44 g ofwater, refluxed for 3-5 h and then quenched with 10 g of acetone. Thesolvents were stripped off under vacuum and the residue was taken up in200 g of water/acetone (2:1). The pH was adjusted to 5.8 to 6.0 by theaddition of acetic acid, causing the fexofenadine base to crystallizeout. The precipitate was filtered off, washed with water and dried undervacuum at 60° C. to give 22 g (83%) of product.

Example 2 Synthesis of Fexofenadine Hydrochloride, Form A

86 g of fexofenadine base were suspended in acetonitrile (700 g), and 30g of a 20.6 percent solution of hydrogen chloride in diisopropyl etherwere added at −10 to −12° C. The reaction mixture was heated at thereflux temperature for 1 h and then cooled. The hydrochloride wasisolated by filtration, washed with acetonitrile and dried under vacuumat 100° C. to give 83 g (90%) of fexofenadine hydrochloride, form A.

Example 3 Synthesis of Fexofenadine Hydrochloride, Form A

10.0 g of fexofenadine base were suspended in acetonitrile (76 g), and1.9 g of a 38.6 percent solution of hydrogen chloride in methanol wereadded at −10 to −12° C. The reaction mixture was heated at the refluxtemperature for 1 h and then cooled. The hydrochloride was isolated byfiltration, washed with acetonitrile and dried under vacuum at 100° C.to give 10.1 g (94%) of fexofenadine hydrochloride, form A.

Example 4 Synthesis of fexofenadine Hydrochloride, Form A

10.0 g of fexofenadine base were suspended in acetonitrile (76 g), and3.7 g of a 19.5 percent solution of hydrogen chloride in ethyl acetatewere added at −10 to −12° C. The reaction mixture was heated at thereflux temperature for 1 h and then cooled. The hydrochloride wasisolated by filtration, washed with acetonitrile and dried under vacuumat 100° C. to give 9.8 g (91%) of fexofenadine hydrochloride, form A.

Example 5 Synthesis of Amorphous Fexofenadine Hydrochloride

10.0 g of fexofenadine base were suspended in n-heptane (90 g), and 4.02g of a 17.9 percent solution of hydrogen chloride in diisopropyl etherwere added at −10 to −12° C. The reaction mixture was heated at thereflux temperature for 1 h and then cooled. The hydrochloride wasisolated by filtration, washed with n-heptane and dried under vacuum at100° C. to give 9.7 g (90%) of amorphous fexofenadine hydrochloride.

Example 6 Synthesis of Amorphous Fexofenadine Hydrochloride

10.0 g of fexofenadine base were suspended in tert-butyl methyl ether(90 g), and 4.0 g of a 17.9 percent solution of hydrogen chloride indiisopropyl ether were added at −10 to −12° C. The reaction mixture washeated at the reflux temperature for 1 h and then cooled. Thehydrochloride was isolated by filtration, washed with tert-butyl methylether and dried under vacuum at 100° C. to give 10.5 g (98%) ofamorphous fexofenadine hydrochloride.

Example 7 Synthesis of Fexofenadine Hydrochloride in the Form of aMixture of Different Polymorphs

5.1 g of fexofenadine base were suspended in acetonitrile (39 g). 0.4 gof hydrogen chloride was passed into the suspension at −10 to −12° C.,after which the mixture was heated at the reflux temperature for 1.5 hand then cooled. The hydrochloride was isolated by filtration, washedwith acetonitrile and dried under vacuum at 00° C. to give 5.1 g (92%)of fexofenadine hydrochloride in the form of a mixture of differentpolymorphs.

1. A non-hydrated fexofenadine hydrochloride in the form of a novelpolymorph (“form A”), wherein the novel polymorph has the following XRDdata: rel. intensity D/Å (I/I_(max))/% 11.8 55 11.2 30 7.5 50 6.6 30 5.920 5.6 70 5.4 20 4.9 65 4.7 100 4.6 35 4.4 40 4.3 100 4.1 40 4.0 30 3.440

and wherein the polymorph has a melting range of 153-156° C.